CN103492393A - 用于制备吡喃并[2,3-c]吡啶衍生物的方法 - Google Patents
用于制备吡喃并[2,3-c]吡啶衍生物的方法 Download PDFInfo
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- BVIHAADUZBOGSJ-UHFFFAOYSA-N 2h-pyrano[2,3-c]pyridine Chemical class N1=CC=C2C=CCOC2=C1 BVIHAADUZBOGSJ-UHFFFAOYSA-N 0.000 title 1
- 238000004519 manufacturing process Methods 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 77
- 238000000034 method Methods 0.000 claims abstract description 28
- 239000003795 chemical substances by application Substances 0.000 claims description 26
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 22
- 230000002829 reductive effect Effects 0.000 claims description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 20
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 11
- -1 methyl Chemical group 0.000 claims description 8
- 150000007530 organic bases Chemical class 0.000 claims description 8
- SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide pyridine complex Chemical compound O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 claims description 3
- 229910010082 LiAlH Inorganic materials 0.000 claims description 3
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- FIYYMXYOBLWYQO-UHFFFAOYSA-N ortho-iodylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I(=O)=O FIYYMXYOBLWYQO-UHFFFAOYSA-N 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 230000018044 dehydration Effects 0.000 claims description 2
- 238000006297 dehydration reaction Methods 0.000 claims description 2
- 208000035143 Bacterial infection Diseases 0.000 abstract 1
- 208000022362 bacterial infectious disease Diseases 0.000 abstract 1
- 239000003153 chemical reaction reagent Substances 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 44
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- 239000002585 base Substances 0.000 description 22
- 238000003756 stirring Methods 0.000 description 18
- 239000012044 organic layer Substances 0.000 description 17
- 239000010410 layer Substances 0.000 description 15
- 239000000243 solution Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 11
- 229910052760 oxygen Inorganic materials 0.000 description 11
- 239000001301 oxygen Substances 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- 238000005406 washing Methods 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
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- 239000003513 alkali Substances 0.000 description 5
- 239000012141 concentrate Substances 0.000 description 5
- OMFXVFTZEKFJBZ-HJTSIMOOSA-N corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
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- 0 *C(*)(C1(*)*)C(*)(*)Oc2c1c(*)c(C(O*)=O)nc2* Chemical compound *C(*)(C1(*)*)C(*)(*)Oc2c1c(*)c(C(O*)=O)nc2* 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 4
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 150000004880 oxines Chemical class 0.000 description 3
- 235000019260 propionic acid Nutrition 0.000 description 3
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 3
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- GNTDGMZSJNCJKK-UHFFFAOYSA-N divanadium pentaoxide Chemical compound O=[V](=O)O[V](=O)=O GNTDGMZSJNCJKK-UHFFFAOYSA-N 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- UIZVMOZAXAMASY-UHFFFAOYSA-N hex-5-en-1-ol Chemical compound OCCCCC=C UIZVMOZAXAMASY-UHFFFAOYSA-N 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- HZDNNJABYXNPPV-UHFFFAOYSA-N (2-chloro-2-oxoethyl) acetate Chemical compound CC(=O)OCC(Cl)=O HZDNNJABYXNPPV-UHFFFAOYSA-N 0.000 description 1
- ZYJPUMXJBDHSIF-NSHDSACASA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ZYJPUMXJBDHSIF-NSHDSACASA-N 0.000 description 1
- QVHJQCGUWFKTSE-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound OC(=O)C(C)NC(=O)OC(C)(C)C QVHJQCGUWFKTSE-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- VTIODUHBZHNXFP-NSCUHMNNSA-N 4-Hexen-1-ol, (E)- Chemical compound C\C=C\CCCO VTIODUHBZHNXFP-NSCUHMNNSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- LOMVENUNSWAXEN-UHFFFAOYSA-N Methyl oxalate Chemical compound COC(=O)C(=O)OC LOMVENUNSWAXEN-UHFFFAOYSA-N 0.000 description 1
- DSOLBHZRAGNEPO-UHFFFAOYSA-N O=Cc(nc1)cc2c1OCCC2 Chemical compound O=Cc(nc1)cc2c1OCCC2 DSOLBHZRAGNEPO-UHFFFAOYSA-N 0.000 description 1
- QXVCUSYHDODUGS-UHFFFAOYSA-N OCc(nc1)cc2c1OCCC2 Chemical compound OCc(nc1)cc2c1OCCC2 QXVCUSYHDODUGS-UHFFFAOYSA-N 0.000 description 1
- 229910004298 SiO 2 Inorganic materials 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- FATAVLOOLIRUNA-UHFFFAOYSA-N formylmethyl Chemical group [CH2]C=O FATAVLOOLIRUNA-UHFFFAOYSA-N 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical group C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- ATYBXHSAIOKLMG-UHFFFAOYSA-N oxepin Chemical compound O1C=CC=CC=C1 ATYBXHSAIOKLMG-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- VTIODUHBZHNXFP-UHFFFAOYSA-N trans-hex-4-en-1-ol Natural products CC=CCCCO VTIODUHBZHNXFP-UHFFFAOYSA-N 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Communicable Diseases (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Cephalosporin Compounds (AREA)
Abstract
Description
背景技术
本发明涉及吡喃并-[2,3-c]吡啶衍生物及其制备方法。公开于WO2004058144中的3,4-二氢-2H-吡喃并[2,3-c]吡啶-6-甲醛,其特征在于下式(VIII):
吡喃并[2,3-c]吡啶衍生物已显示出其可以作为用于治疗细菌感染的化合物的有用的中间体。此前公开的用于制备吡喃-[2,3-c]吡啶-6-甲醛的方法是困难的,其需要使用昂贵的原料的许多步骤,以及产生不理想的总产率。(参见WO2003042210,实施例18;WO2004058144,实施例126(a)-(e))。因此发现从相对廉价的化学制品制备该构建块的替代方法将是十分有利的。
发明概述
一方面,本发明是方法,其包括用合适的脱水剂将式(I)化合物脱水:
以形成式(II)化合物:
其中R1是-CH=CH-R8或-CH2-CH=CH-R9;
R2是C1-C4-烷基;
R3是H、C1-C4-烷基、苄基、-苯基-(R10)x,或-C1-C4-烷基-COO-C1-C4-烷基;
每个R4独立地是H,或C1-C4-烷基;
每个R5和每个R6独立地为H、C1-C4-烷基、-O-C1-C4-烷基,或-S-C1-C4-烷基;
R7为R8或-CH2-R9;
R8是H、C1-C4-烷基、-苯基-(R10)x,或-COO-C1-C4-烷基;
R9是H、C1-C3-烷基、-苯基-(R10)x,或-COO-C1-C4-烷基;
每个R10独立地是卤素、C1-C4-烷基、-O-C1-C6-烷基,或-S-C1-C4-烷基;并且每个x独立地是0、1、或2。
在另一方面,本发明为方法,其包括用合适的脱水剂将式(V)化合物脱水的步骤:
以形成式(VI)化合物:
其中R2是C1-C4-烷基。式(II)化合物已经显示可以作为用于治疗细菌感染的化合物的中间体。
发明详述
在第一方面,本发明是方法,其包括用合适的脱水剂将式(I)化合物脱水:
以形成式(II)化合物:
其中R1-R7如前面所定义。
本文中使用的C1-C4-烷基是指具有高至4个碳原子的直链或支链烷基。示例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基,和叔丁基。类似地,C1-C3-烷基是指甲基、乙基、正丙基,或异丙基。
在另一实施方案中,R4、R5和R6各自独立地为H或C1-C4-烷基。
在另一实施方案中,R4、R5和R6各自独立地为H或甲基。
在另一实施方案中,R4、R5和R6的每一个为H。
合适的脱水剂的实例包括三氟甲磺酸酐(Tf2O)和五氧化二磷(P2O5),优选Tf2O。化合物(I)至化合物(II)[或化合物(V)至化合物(VI)]的反应在合适的碱,优选为有机碱如吡啶、三乙胺或二异丙基乙胺的存在下进行是有利的。优选地,使用的碱的范围为相对于化合物(I)1当量至小于以当量计的脱水剂的量。
式(Ia)化合物:
通过例如,在合适的碱优选有机碱存在下,C1-CO-CO2-R2与式(4)化合物的反应来制备:
其中R8如前面所定义。
式(4)化合物可以在合适的脱保护条件下将式(3)化合物脱保护来制备:
优选通过与强酸,如HCl、H2SO4、MsOH或TsOH反应进行脱保护。
式(3)化合物可以在合适的缩合条件下,例如,在1,1′-羰基二咪唑存在下,通过将式(1)化合物:
式(Ib)化合物:
可以以类似式(Ia)化合物的方式制备,其中R9如前所定义。
式(II)化合物:
可与适宜的还原剂接触而形成式(III)化合物:
合适的还原剂的实例包括二异丁基氢化铝、LiAlH4、LiBH4和NaBH4。
式(III)化合物可与合适的氧化剂接触以形成式(IV)化合物:
合适的氧化剂的实例包括MnO2、Swern氧化剂、2-碘酰基苯甲酸、吡啶三氧化硫和Dess-Martin氧化剂。
可选地,式(IV)化合物:
可以通过用合适的还原剂如二异丁基氢化铝还原式(II)化合物来制备:
方案
方案1示出本发明一个方面。可以通过在合适的缩合条件下,例如在1,1′-羰基二咪唑存在下使酸(1)与醇(2)接触来制备化合物(3)。在合适的脱保护条件下从化合物(3)中除去保护基团以形成胺(4),优选通过与强酸,如HCl、H2SO4、MsOH或TsOH反应来除去保护基团。
式(Ia)化合物可以通过在合适的碱优选有机碱如三乙胺存在下将胺(4)与X-CO-CO2-R2(X=卤素或-OCH3)接触来制备。
式(IIa)化合物可以通过用合适的碱和脱水剂例如吡啶和Tf2O处理式(Ia)化合物来制备。
式(IVa)化合物可以通过至少两个方法制备。例如,式(IIa)化合物可以使用合适的还原剂如二异丁基氢化铝、LiAlH4、LiBH4或NaBH4还原为醇(IIIa)。醇(IIIa)然后可以通过使用合适的氧化剂,如MnO2,Swern氧化剂,2-碘酰基苯甲酸,吡啶三氧化硫或Dess-Martin氧化剂氧化以形成式(IVa)化合物。
可选地,可以用合适的还原剂如二异丁基氢化铝还原式(IIa)化合物来形成式(IVa)化合物。
方案1
方案2中示出本发明的另一个实施方案。式(IVb)化合物可以从醇(6)开始以类似方案1中的化合物的方式来制备。
方案2
实施例
以下实施例是本发明方法的示例性说明,其不旨在限制本发明的范围。
实施例1:3,4-二氢-2H-吡喃并[2,3-c]吡啶-6-甲酸甲酯
(a)2-氧代-2-((2-氧代-2-(戊-4-烯-1-基氧基)乙基)氨基)乙酸甲酯
向1升的反应器中投入1,1′-羰基二咪唑(CDI)(44.0克,0.95当量)及叔丁基甲基醚(TBME)(150mL)。将混合物搅拌下加热至~40℃,于是加入N-Boc-甘氨酸(50克,1当量)在TBME(200mL)中的溶液并继续搅拌0.5小时。然后在30分钟内加入戊-4-烯-1-醇(23克,0.95当量),并在40℃继续搅拌2小时,然后冷却到20℃。加入1N盐酸(125毫升)溶液,以形成两相混合物。将各层分离,并用1N HCl(1×125毫升),然后用水(1×125毫升)洗涤有机层。TBME被蒸馏除去然后将粗品2-((叔丁氧羰基)氨基)乙酸戊-4-烯-1-酯与甲苯(200mL)共沸干燥。将混合物加热至40℃并加入足够的甲苯使甲苯总体积至~200毫升。
加入甲磺酸(34克,1.25当量),并将该混合物在40℃下搅拌2小时,然后冷却至20℃。然后将混合物转移到一个含有草酸二甲酯(34克,1当量)的容器中,且容器的温度在搅拌下保持在20℃。然后将三乙胺(43克,1.5当量)加入到该混合物中搅拌再继续1小时。用水(125毫升)洗涤该混合物。通过共沸干燥浓缩甲苯溶液,得到2-氧代-2-((2-氧代-2-(戊-4-烯-1-基氧基)乙基)氨基)乙酸甲酯的油状物。1H NMR(400MHz,CDCl3)δppm 7.55(s,1H),5.73-5.86(m,1H),4.97-5.10(m,2H),4.21(t,J=6.65Hz,2H),4.13(d,J=5.52Hz,2H),3.93(s,3H),2.13(q,J=7.42Hz,2H),1.71-1.85(m,2H);13C NMR(75MHz,CDCl3)δppm 168.58,160.35,156.29,137.05,115.56,65.25,53.72,41.48,29.84,27.56;HRMS(M+Na)m/z,C10H15NO5Na的计算值:252.0848;实验值:252.0852。
(b)标题化合物
将2-氧代-2-((2-氧代-2-(戊-4-烯-1-基氧基)乙基)氨基)乙酸甲酯(42.5克,1当量)和二氯甲烷(DCM)(425毫升)加入搅拌下的容器中,然后加入吡啶(17.6克,1.2当量)。在45分钟内加入Tf2O(78.5克,1.5当量)至混合物中,保持内部温度为~25℃。将混合物搅拌6小时,在该点,通过加入20wt%的NaOAc水溶液(255毫升)小心地淬灭反应,以形成两相溶液。用DCM(85毫升)萃取水层。先用水(127.5毫升)和10wt%的柠檬酸溶液(170毫升)洗涤合并的有机层。向混合物中加入6N HCl(127.5毫升),以形成两相混合物。分离两层,有机层用6N盐酸(85毫升)萃取。将上述酸性水层合并,并加入DCM(127.5毫升)。同时保持温度低于25℃,缓慢地加入28wt%的NH4OH水溶液,直到水层的pH达到3-5。分离两层,并用DCM(85毫升)萃取水层。将合并的有机层用水(85毫升)洗涤。在减压下浓缩该有机溶液,以提供标题化合物,为油状物,将其静置固化。1H NMR(400MHz,CDCl3)δppm 8.17(s,1H),7.80-7.86(m,1H),4.26(t,J=5.19Hz,2H),3.92(s,3H),2.79(t,J=6.44Hz,2H),1.97-2.09(m,2H);13CNMR(75MHz,CDCl3)δppm 165.11,154.25,138.95,138.64,130.06,126.13,65.55,51.99,23.57,20.67;HRMS(M+Na)m/z,C10H11NO3Na的计算值:216.0637;实验值:216.0643。
实施例2:8-甲基-3,4-二氢-2H-吡喃并[2,3-c]吡啶-6-甲酸乙酯
(a)2-(2-乙氧基-2-氧代乙酰胺基)丙酸戊-4-烯-1-酯
搅拌下将N-(叔丁氧羰基)丙氨酸(3.1克,1当量)和DCM(50mL)加入到容器中,然后加入CDI(3.1克,1.15当量)。该混合物在环境温度下搅拌18小时后,加入4-戊烯-1-醇(1.8克,1.25当量)。将混合物再在环境温度下搅拌18小时,在该点用1N盐酸淬灭反应。形成两相混合物,并分离各层。用饱和NaHCO3水溶液洗涤有机层,然后浓缩得到2-((叔丁氧羰基)氨基)丙酸戊-4-烯-1-酯,为油状物。将该油状物溶解于DCM(50毫升)并加入甲磺酸(2.2克,1.4当量)。将该混合物在环境温度下搅拌~22小时,然后在冰/水浴中冷却。加入2-氯-2-氧代乙酸乙酯(3.4克,1.5当量),随后逐滴加入三乙胺(5.0克,3当量)。将混合物搅拌7小时,之后用1N盐酸将反应淬灭,以形成两相混合物。分离层,并用饱和NaHCO3水溶液洗涤有机层。然后在减压下浓缩有机层,以提供2-(2-乙氧基-2-氧代乙酰胺基)丙酸戊-4-烯-1-酯,为黄色油状物。1H NMR(400MHz,CDCl3)δppm 7.64(d,J=6.94Hz,1H),5.66-5.83(m,1H),4.90-5.05(m,2H),4.49-4.62(m,1H),4.31(qd,J=7.17,2.26Hz,2H),4.13(td,J=6.59,2.13Hz,2H),2.02-2.14(m,2H),1.67-1.78(m,2H),1.44(d,J=7.19Hz,3H),1.34(t,J=7.15Hz,3H);13C NMR(75MHz,CDCl3)δppm 171.64,159.94,155.83,136.94,115.40,64.98,63.10,48.40,29.71,27.44,17.88,13.80;HRMS(M+Na)m/z,C12H19NO5Na的计算值:280.1161;实验值:280.1166.
(b)标题化合物
在搅拌下将2-(2-乙氧基-2-氧代乙酰胺基)丙酸戊-4-烯-1-酯(1.05克,1当量)和DCM(15mL)添加到容器中。然后加入吡啶(0.39克,1.2当量),并将该混合物冷却至15℃。将Tf2O(1.7克,1.5当量)在15分钟内加入到该混合物中,将混合物升温至环境温度,搅拌1.5小时。通过加入DCM和20wt%NaOAc水溶液将反应淬灭,形成两相混合物。分离层,将有机层用水洗涤。然后在减压下浓缩有机层,以提供标题化合物,为黄色固体。1HNMR(300MHz,CDCl3)δppm 7.62(s,1H),4.32(q,J=7.12Hz,2H),4.16-4.25(m,2H),2.70(t,J=6.44Hz,2H),2.37(s,3H),1.86-2.03(m,2H),1.31(t,J=7.12Hz,3H);13CNMR(75MHz,CDCl3)δppm165.15,152.44,147.98,137.72,128.73,124.80,66.85,61.09,23.98,21.06,18.98,14.11;HRMS(M+H)m/z,C12H16NO3的计算值:222.1130;实验值:222.1133。
实施例3:8-苄基-3,4-二氢-2H-吡喃并[2,3-c]吡啶-6-甲酸乙酯
(a)2-(2-乙氧基-2-氧代乙酰胺基)-3-苯基丙酸戊-4-烯-1-酯
2-(2-乙氧基-2-氧代乙酰胺基)-3-苯基丙酸戊-4-烯-1-酯以类似实施例2(a)的方式制备,从N-(叔丁氧羰基)苯丙氨酸开始(1.0克)。1H NMR(400MHz,CDCl3)δppm7.52(d,J=8.03Hz,1H),7.28-7.37(m,3H),7.15-7.19(m,2H),5.73-5.84(m,1H),5.06-5.10(m,1H),5.01-5.05(m,1H),4.87-4.95(m,1H),4.38(qd,J=7.15,1.72Hz,2H),4.11-4.21(m,2H),3.21(d,J=6.11Hz,2H),2.05-2.13(m,2H),1.69-1.79(m,2H),1.41(t,J=7.15Hz,3H);13C NMR(75MHz,CDCl3)δppm 170.30,159.85,155.93,137.01,135.14,129.10,128.62,127.26,115.43,65.10,63.22,53.57,37.70,29.75,27.42,13.85;HRMS(M+H)m/z,C18H24NO5的计算值334.1654;实验值:334.1665。
(b)标题化合物
将2-(2-乙氧基-2-氧代乙酰胺基)-3-苯基丙酸戊-4-烯-1-酯(0.80克,1当量)和DCM(15mL)在搅拌下加入容器中。然后加入吡啶(0.23克,1.2当量),并将该混合物冷却至15℃。将Tf2O(1.0克,1.5当量)在15分钟内加入到该混合物中,并将该混合物加热至环境温度。将该溶液搅拌3.5小时后,通过DCM和20wt%NaOAc水溶液将该反应淬灭,形成两相混合物。分离各层,将有机层用6N盐酸(3×10毫升)萃取。合并的酸层用DCM洗涤,用固体K2CO3将pH调节至~9。碱性水层用DCM萃取。在减压下浓缩有机层,以提供标题化合物。1H NMR(300MHz,CDCl3)δppm 7.74(s,1H),7.10-7.35(m,5H),4.43(q,J=7.12Hz,2H),4.22-4.29(m,2H),4.21(s,2H),2.78(t,J=6.41Hz,2H),1.93-2.06(m,2H),1.41(t,J=7.12Hz,3H);13C NMR(75MHz,CDCl3)δppm 165.08,152.25,149.62,138.86,138.06,129.62,128.61,127.80,125.61,125.23,66.70,60.97,38.55,23.93,20.92,14.10;HRMS(M+H)m/z,C18H20NO3的计算值:298.1443;实验值:298.1450。
实施例4:8-苯基-3,4-二氢-2H-吡喃并[2,3-c]吡啶-6-甲酸乙酯
(a)2-氧代-2-((2-氧代-2-(戊-4-烯-1基氧基)-1-苯基乙基)氨基)乙酸乙酯
2-氧代-2-((2-氧代-2-(戊-4-烯-1-基氧基)-1-苯基乙基)氨基)乙酸乙酯以类似实施例2(a)的方式制备,从α-[[(1,1-二甲基乙氧基)羰基]氨基]-苯乙酸(0.96克)开始。1HNMR(400MHz,CDCl3)δppm 8.01(d,J=7.11Hz,1H),7.32-7.43(m,5H),5.63-5.78(m,1H),5.58(d,J=7.61Hz,1H),4.88-4.98(m,2H),4.36(q,J=7.11Hz,2H),4.11-4.24(m,2H),1.93-2.04(m,2H),1.70(qd,J=7.12,6.88,2.05Hz,2H),1.39(t,J=7.15Hz,3H);13C NMR(75MHz,CDCl3)δppm 169.75,159.93,155.72,136.94,135.47,129.02,128.83,127.26,115.53,65.40,63.32,56.69,29.63,27.44,13.91;HRMS(M+H)m/z,C17H22NO5的计算值:320.1498;实验值:320.1512。
(b)标题化合物
8-苯基-3,4-二氢-2H-吡喃并[2,3-c]吡啶-6-甲酸乙酯以与实施例3(b)类似的方式制备,从2-氧代-2-((2-氧代-2-(戊-4-烯-1-基氧基)-1-苯基乙基)氨基)乙酸乙酯(0.91克)开始。1H NMR(300MHz,CDCl3)δppm 7.91-7.98(m,2H),7.84(s,1H),7.34-7.49(m,3H),4.44(q,J=7.12Hz,2H),4.29-4.38(m,2H),2.91(t,J=6.44Hz,2H),2.02-2.18(m,2H),1.43(t,J=7.12Hz,3H);13C NMR(75MHz,CDCl3)δppm165.11,152.06,149.30,146.60,138.65,136.72,135.82,130.64,129.30,128.06,127.59,125.48,66.89,61.07,24.37,20.84,14.09;HRMS(M+H)m/z,C17H18NO3的计算值284.1287;实验值:284.1301。
实施例5:5-甲基-3,4-二氢-2H-吡喃并[2,3-c]吡啶-6-甲酸甲酯
(a)(E)-2-((2-(己-4-烯-1-基氧基)-2-氧代乙基)氨基)-2-氧代乙酸甲酯
向保持在40℃的容器中投入CDI(2.75克,0.95当量)和TBME(9mL)。搅拌下在30分钟内向此混合物中加入溶于TBME(12mL)中的N-(叔丁氧羰基)甘氨酸(3.1克,1.0当量)的溶液。继续搅拌另外30分钟,于是在30分钟内加入反式-4-己烯-1-醇(1.7克,0.95当量)。将混合物保持于40℃下搅拌另外3.5小时,然后冷却至环境温度并进一步搅拌14小时。用1N HCl(2×7.8毫升),然后用水(1×7.8毫升)洗涤该混合物。用Na2SO4干燥有机层,过滤并浓缩,得到(E)-2-((叔丁氧羰基)氨基)乙酸己-4-烯-1-酯,为油状物。该油状物溶解于DCM(12毫升)并逐滴加入4.0M HCl/二噁烷(2.8毫升)。该混合物在环境温度下搅拌1.5小时,然后将混合物加热到35℃,并搅拌3小时。逐滴加入4.0M HCl/二噁烷(2.8毫升)。在35℃下,6小时后逐滴加入进一步剂量的4.0M HCl/二噁烷(2.8毫升),并将该混合物再搅拌4小时。将混合物冷却至环境温度,并在减压下除去溶剂。残余物的一部分(1.0克)溶解于DCM(8mL)并加入2-氯-2-氧代乙酸甲酯(0.63克)。在20分钟内逐滴加入三乙胺(1.0克)。将混合物搅拌1小时,然后用1NHCl(2.5毫升)淬灭,以形成两相混合物。分离各层,将有机层用1N盐酸(1×2.5毫升),水(1×2.5毫升)洗涤,并在减压下浓缩以提供油状物。快速柱色谱(SiO2,10->60%乙酸乙酯/己烷梯度)提供标题化合物,为油状物形式的反式:顺式异构体的95∶5混合物。1H NMR(300MHz,CDCl3)δppm 7.57(s,1H),5.31-5.55(m,2H),4.17(t,J=6.69Hz,2H),4.12(d,J=5.51Hz,2H),3.92(s,3H),1.97-2.10(m,2H),1.67-1.77(m,2H),1.62-1.67(m,3H);13C NMR(75MHz,CDCl3)δppm 168.60,160.35,156.28,129.49,126.12,65.34,53.68,41.47,28.62,28.17,17.84;HRMS(M+H)m/z,C11H18NO5的计算值:244.1185;实验值:244.1187。
(b)标题化合物
搅拌下,将(E)-2-((2-(己-4-烯-1-基氧基)-2-氧代乙基)氨基)-2-氧代乙酸甲酯(0.24克,1当量)和DCM(2.4毫升)加入到容器中,再加入吡啶(95毫克,1.2当量)。然后在环境温度下在45分钟加入Tf2O(0.42克,1.5当量),并将该混合物在环境温度下搅拌48小时。混合物用20wt%的醋酸钠水溶液(2×1.5毫升),10wt%柠檬酸水溶液(3×1.5ml),和水(1×1.5毫升)洗涤。然后在减压下浓缩有机层,以提供固体的标题化合物。1H NMR(300MHz,CDCl3)δppm 8.10(s,1H),4.15-4.25(m,2H),3.94(s,3H),2.71(t,J=6.56Hz,2H),2.47(s,3H),2.00-2.18(m,2H);13CNMR(75MHz,CDCl3)δppm 166.71,153.50,138.69,136.72,135.67,130.36,65.93,52.35,22.18,21.49,14.57;HRMS(M+H)m/z,C11H14NO3的计算值:208.0974;实验值:208.0981。
实施例6:5-甲基-3,4-二氢-2H-吡喃并[2,3-c]吡啶-6-甲酸乙酯
(a)2-((2-(己-5-烯-1-基氧基)-2-氧代乙基)氨基)-2-氧代乙酸乙酯
2-((2-(己-5-烯-1-基氧基)-2-氧代乙基)氨基)-2-氧代乙酸乙酯以类似于实施例2(a)的方式制备,从N-(叔丁氧羰基)甘氨酸(2.8克)和5-己烯-1-醇(2.08克)开始。1HNMR(300MHz,CDCl3)δppm 7.60(s,1H),5.66-5.86(m,1H),4.88-5.06(m,2H),4.35(q,J=7.12Hz,2H),4.17(t,J=6.63Hz,2H),4.11(d,J=5.57Hz,2H),2.06(q,J=7.16Hz,2H),1.59-1.72(m,2H),1.39-1.51(m,2H),1.37(t,J=7.15Hz,3H);13CNMR(75MHz,CDCl3)δppm 168.67,159.84,156.57,138.00,114.93,65.66,63.25,41.41,33.07,27.77,24.91,13.88;HRMS(M+H)m/z,C12H20NO5的计算值:258.1341;实验值:258.1349。
(b)标题化合物(A)
2-((2-(己-5-烯-1-基氧基)-2-氧代乙基)氨基)-2-氧代乙酸乙酯(0.35克)和DCM(4毫升)在搅拌下加入到容器中,再加入吡啶(0.13克)。然后在环境温度下将Tf2O(0.58克)缓慢加入到混合物中。将该混合物在环境温度下搅拌4天,之后将混合物用6N盐酸(3×10毫升)萃取。合并的酸层用DCM(10mL)洗涤,并用固体K2CO3将pH调节至~10。碱性水层用DCM(20毫升)萃取。在减压下浓缩有机层,以提供基于NMR分析的标题化合物(A)和2,3,4,5-四氢氧杂环庚三烯并[2,3-c]吡啶-7-甲酸乙酯(B)的3∶1的混合物。1HNMR(300MHz,CDCl3)δppm 8.38(s,0.3H,化合物B),8.11(s,1H,化合物A),7.95(s,0.3H,化合物B),4.36-4.51(m,2.6H,化合物A/B CH3CH2),4.17-4.25(m,2H,化合物A OCH2),4.06-4.13(m,0.6H,化合物B OCH2),2.85-2.93(m,0.6H,化合物B CH2),2.71(t,J=6.53Hz,2H,化合物A CH2),2.45(s,3H,化合物A CH3),1.99-2.15(m,2.6H,化合物A/B CH2),1.54-1.88(m,0.6H,化合物B CH2),1.44(t,J=7.12Hz,0.9H,化事物B CH3),1.44(t,J=7.12Hz,3H,化合物A CH3);13C NMR(75MHz,CDCl3)δppm 166.53,165.01,162.88,159.21,153.21,143.48,143.11,142.72,139.52,136.74,134.94,130.12,127.21,73.82,65.85,61.61,61.21,33.74,31.53,24.97,22.11,21.48,14.56,14.28;化合物A:HRMS(M+Na)m/z,C12H15NO3Na的计算值:244.0950;实验值:244.0961;化合物B:HRMS(M+H)m/z,C12H16NO3的计算值:222.1130;实验值:222.1130。
实施例7:3,4-二氢-2H-吡喃并[2,3-c]吡啶-6-甲醛
(a)(3,4-二氢-2H-吡喃并[2,3-c]吡啶-6-基)甲醇
向容器中在搅拌下加入3,4-二氢-2H-吡喃并[2,3-c]吡啶-6-甲酸甲酯(7.4克,1当量)和四氢呋喃(THF)(32毫升)。加热混合物到55℃,随后在1小时内加入2M的LiBH4的THF溶液(20毫升,1.05当量)。在55℃继续搅拌直到还原完全,在该点,将混合物冷却至45℃并将6N盐酸(37毫升)小心地加入到混合物中。继续搅拌1小时,然后将混合物冷却至25℃。用50wt%NaOH水溶液将pH调节到~9.5至10。用2-甲基四氢呋喃(2×37毫升)萃取有机物。将合并的有机层在减压下浓缩和结晶,以提供作为灰白色固体的(3,4-二氢-2H-吡喃并[2,3-c]吡啶-6-基)甲醇。1H NMR(300MHz,CDCl3)δppm 8.10(s,1H),6.91-6.99(m,1H),4.65(s,2H),4.18-4.29(m,2H),3.42(s,1H),2.79(t,J=6.50Hz,2H),1.96-2.12(m,2H);13C NMR(75MHz,CDCl3)δppm 151.09,150.39,137.87,131.40,121.14,66.51,64.10,24.22,21.55;HRMS(M+H)m/z,C9H12NO2的计算值:166.0868;实验值:166.0861。
(b)标题化合物
搅拌下将(3,4-二氢-2H-吡喃并[2,3-c]吡啶-6-基)甲醇(300克,1.0当量)、DCM(1.5L)和二甲基亚砜(216毫升,2.05当量)加入保持在~0~5℃的容器。将三乙胺(858毫升,4.1当量)然后是固体吡啶三氧化硫(474克,2.0当量)缓慢加入到混合物中,同时保持混合物温度在~0至7℃。在~0~7℃搅拌混合物~5至8小时,然后用5wt%NaHCO3水溶液(3L)淬灭,以形成两相混合物。分离各层,并用DCM(0.9升)萃取水层。将合并的有机层用5wt%的柠檬酸水溶液(3.0升)和盐水(300毫升)洗涤,用无水硫酸钠干燥,并过滤,以提供标题化合物的DCM溶液。1H NMR(300MHz,CDCl3)δppm 9.94(s,1H),8.21-8.32(m,1H),7.72(s,1H),4.25-4.40(m,2H),2.85(t,J=6.50Hz,2H),1.97-2.19(m,2H)。
Claims (17)
1.方法,其包括用合适的脱水剂将式(I)化合物脱水:
以形成式(II)化合物的步骤:
其中R1是-CH=CH-R8或-CH2-CH=CH-R9;
R2是C1-C4-烷基;
R3是H、C1-C4-烷基、苄基、-苯基-(R10)x,或-C1-C4-烷基-COO-C1-C4-烷基;
每个R4独立地是H或C1-C4-烷基;
每个R5和每个R6独立地为H、C1-C4-烷基、-O-C1-C4-烷基,或-S-C1-C4-烷基;
R7为R8或-CH2-R9;
R8是H、C1-C4-烷基、-苯基-(R10)x,或-COO-C1-C4-烷基;
R9是H、C1-C3-烷基、-苯基-(R10)x,或-COO-C1-C4-烷基;
每个R10独立地是卤素、C1-C6-烷基、-O-C1-C4-烷基,或-S-C1-C4-烷基;并且每个x独立地是0、1或2。
2.如权利要求1所述的方法,其进一步在有机碱存在下进行,其中所述脱水剂是Tf2O或P2O5;以及R4、R5和R6各自独立地为H或C1-C4-烷基。
3.如权利要求2所述的方法,其中R4、R5和R6各自独立地为H或甲基;和有机碱是吡啶、三乙胺或二异丙基乙胺。
4.如权利要求2或3所述的方法,其中R4、R5和R6中的每一个是H;所述脱水剂是Tf2O;使用的有机碱的量为相对于化合物(I)至少1当量并且小于脱水剂的量,以当量计。
8.如权利要求7所述的方法,其中所述脱水剂是Tf2O或P2O5。
9.如权利要求7或8所述的方法,其中所述脱水剂是Tf2O;和R2是甲基或乙基。
10.如权利要求7、8或9所述的方法,其中所述方法在有机碱存在下进行,所述有机碱的量为相对于化合物(V)至少1当量并小于脱水剂的量,以当量计。
13.如权利要求5或11所述的方法,其中所述还原剂是二异丁基氢化铝、LiAlH4、LiBH4或NaBH4。
14.如权利要求5、11或13所述的方法,其中所述还原剂是LiBH4。
15.如权利要求5、11、13或14所述的方法,其中所述氧化剂是MnO2、Swern氧化剂、2-碘酰基苯甲酸、吡啶三氧化硫或Dess-Martin氧化剂。
16.如权利要求5、11、13、14或15所述的方法,其中所述氧化剂是吡啶三氧化硫。
17.如权利要求6或12所述的方法,其中所述还原剂是二异丁基氢化铝。
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